Incomplete understanding as to how HIV influences TB transmission dynamics in Africa represents a major gap in knowledge and a significant obstacle to disrupting TB transmission. Characterizing recent TB transmission networks, identifying sites of ongoing TB transmission, and understanding how HIV influences TB transmission are all critical steps in developing novel, strategic intensified TB case-finding approaches in Africa. Our central hypotheses are that the majority of recent TB transmission in this high HIV prevalence setting takes place in community gathering and health care sites, as opposed to households, and HIV-infected persons are at significantly increased risk of recent TB transmission compared to HIV-uninfected persons. The objectives of the current proposal are the following: Aim 1: Identify and characterize recent TB transmission networks in an East African rural setting. We will perform molecular epidemiologic analysis of all diagnosed, culture-positive TB cases initiating TB therapy in Tororo Municipality over 3 years (~360) in order to identify recent TB transmission networks defined by genotypic clustering of TB isolates. Aim 2: Locate sites of frequent TB transmission through analysis of the geographic distribution and social networks of genotype-clustered incident TB cases. We will combine molecular epidemiologic, geospatial and social network data to identify TB transmission "hot spots", characterized by high levels of TB transmission. These "hot spots" may occur in commercial, social (e.g. markets, bars, churches), or health care settings. We will investigate how HIV influences where TB is transmitted at a community level Aim 3: Pilot test a place-based intensified TB case-finding strategy at two identified locations of high TB transmission risk. Through a focused program of mentored training and coursework, the candidate will develop advanced skills in molecular epidemiology, Geographic Information System (GIS) analysis and the spatial analysis of epidemiologic data, social network analysis, and the conduct of prospective clinical studies in resource-limited settings. These scientific and career aims will serve as the basis for the long term research goal of conducting large, community-wide trials of targeted intensified TB case-finding in sub-Saharan Africa in order to reduce TB mortality and transmission among HIV-infected and uninfected persons. PUBLIC HEALTH RELEVANCE (provided by applicant): This project will advance our understanding of how TB is spreading through a rural community with a generalized HIV epidemic in East Africa and serve as the foundation for developing novel ways to disrupt TB transmission and reduce TB mortality through early diagnosis and intensified case-finding, a goal of significant scientific and public health importance. Identification of the location of community "hot-spots" of TB transmission by HIV status gives us the opportunity to pilot test interventions to identify new TB cases and stop subsequent transmission of TB. Data from this study will be highly useful to the design and implementation of community-based intensified TB case-finding approaches in sub-Saharan Africa for future R01 studies.